Our studies have demonstrated the potential of anti-idiotypic antibodies (Ab2) as immunizing agents for cancer patients to induce tumor-specific immunity. Ab2 as active immunizing agents for cancer patients offer several advantages over tumor-derived compounds: Ab2 vaccines are safe, highly specific and easy to produce in large quantities. Most importantly, Ab2, because they can break immunological tolerance to antigen, may be very useful in cancer patients who are often tolerant of antigen expressed by their own growing tumors. In a phase I clinical trial in patients with colorectal carcinoma (CRC) polyclonal goat Ab2 directed against anti-CRC antibody CO17-1A (Ab1) were shown to induce anti-anti-idiotypic antibodies (Ab3) that were Ab1-like in their binding specificity to tumor cells and antigen. However, the fraction of antigen- binding Ab3 was low among all antibodies produced by the patients against Ab2. This may be due to the polyclonality of the Ab2. To generate a more specific Ab2 vaccine, a monoclonal Ab2 was produced in rats (under NIH grant 1 R01 CA-43735) against Ab1 CO17-1A. In Preclinical studies the monoclonal Ab2 was superior to the polyclonal Ab2 in its capacity to induce antigen-specific Ab3. This Ab2, therefore, is a candidate vaccine for cancer patients. In the phase I clinical trial proposed here, the monoclonal Ab2 will be administered to up to 32 patients with untreatable CRC. The goal of this trial is to demonstrate the immunomodulatory activity of the Ab2 in the patients. Initially, the dose of Ab2 that will induce Ab2-binding antibodies in >75% of the patients will be determined in up to 16 patients. This dose will then be administered to additional (up to 16) patients to demonstrate a >50% response rate in the induction of tumor cell-binding Ab3. Ab3 circulating in patients' blood will be further characterized as to their idiotope and epitope specificities. Ab3 also will be tested for cytolytic activity against tumor cells in vitro. To investigate whether Ab2 immunotherapy induces antigen-specific helper and/or cytolytic T cells, patients' peripheral blood lymphocytes will be stimulated in culture with Ab2, antigen or autologous cultured tumor cells followed by testing of proliferative response and cytolytic activities of the stimulated cells. Although this is a phase I trial with emphasis on patients' immune responses, patients with measurable disease will be monitored and the response of their tumor assessed. Possible effects of Ab2 immunizations on growth of CRC will be related to the patients' immunological responses.